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1.
BMC Med Res Methodol ; 23(1): 184, 2023 08 14.
Article in English | MEDLINE | ID: mdl-37580666

ABSTRACT

BACKGROUND: Declining response proportions in surveys have been observed internationally. Improving response proportions is important for the generalizability of the outcome. The aim of this study was to examine the potential of animation videos to improve response proportions and sample composition in health surveys. METHODS: A randomized trial was embedded in the Danish National Health Survey 2021 (n = 186,113) where the use of animation videos in the digital invitation letter was tested as a mean to increase response proportion. The effect of both demographic-targeted videos and a general video was tested. The sample was stratified into four subsamples; (1) individuals with non-western background and a non-Danish citizenship (n = 9,956), (2) men aged 16-24 years (n = 12,481), (3) women aged 75 years or older (n = 7,815) and (4) the remaining individuals (n = 155,861). The fourth subsample was randomized into two equal sized groups; a group receiving the general video and a control group receiving no video. Each of the first three subsamples was subsequently randomized into three subgroups with 25% receiving the target group video, 25% receiving the general video and 50% receiving no video. A total of four reminders (one digital and three postal) were sent to the eligible population. RESULTS: The use of animation videos resulted in similar or slightly lower overall response proportion compared to the control group. The different animation videos were found to have heterogeneous effects on response proportions. A positive effect was found among men aged 16-24 years before the delivery of the postal reminder for the targeted animation video compared to no video (odds ratio: 1.13; 95% confidence interval: 1.02-1.26). Overall, the targeted animation videos tended to produce higher response proportions than the general animation video. CONCLUSIONS: The heterogeneous effects of the videos suggest that there is some potential for the use of animation videos to improve response proportions and sample composition. The content, target group and timing of evaluation seem to be important for the animation videos to be successful. This warrants further research to better identify in which contexts, in which subgroups and under which circumstances, animation videos are useful to increase response proportions. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05520242, registered 08/26/2022.


Subject(s)
Health Surveys , Male , Humans , Female , Surveys and Questionnaires , Odds Ratio
2.
J Biol Chem ; 298(9): 102317, 2022 09.
Article in English | MEDLINE | ID: mdl-35926706

ABSTRACT

The Na+,K+-ATPase generates electrochemical gradients of Na+ and K+ across the plasma membrane via a functional cycle that includes various phosphoenzyme intermediates. However, the structure and function of these intermediates and how metal fluorides mimick them require further investigation. Here, we describe a 4.0 Å resolution crystal structure and functional properties of the pig kidney Na+,K+-ATPase stabilized by the inhibitor beryllium fluoride (denoted E2-BeFx). E2-BeFx is expected to mimic properties of the E2P phosphoenzyme, yet with unknown characteristics of ion and ligand binding. The structure resembles the E2P form obtained by phosphorylation from inorganic phosphate (Pi) and stabilized by cardiotonic steroids, including a low-affinity Mg2+ site near ion binding site II. Our anomalous Fourier analysis of the crystals soaked in Rb+ (a K+ congener) followed by a low-resolution rigid-body refinement (6.9-7.5 Å) revealed preocclusion transitions leading to activation of the dephosphorylation reaction. We show that the Mg2+ location indicates a site of initial K+ recognition and acceptance upon binding to the outward-open E2P state after Na+ release. Furthermore, using binding and activity studies, we find that the BeFx-inhibited enzyme is also able to bind ADP/ATP and Na+. These results relate the E2-BeFx complex to a transient K+- and ADP-sensitive E∗P intermediate of the functional cycle of the Na+,K+-ATPase, prior to E2P.


Subject(s)
Beryllium , Cardiac Glycosides , Fluorides , Kidney , Sodium-Potassium-Exchanging ATPase , Adenosine Diphosphate/metabolism , Adenosine Triphosphate/metabolism , Animals , Beryllium/chemistry , Cardiac Glycosides/chemistry , Fluorides/chemistry , Kidney/enzymology , Kinetics , Phosphates/metabolism , Phosphorylation , Protein Domains , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/chemistry , Swine
3.
Animals (Basel) ; 12(12)2022 Jun 15.
Article in English | MEDLINE | ID: mdl-35739888

ABSTRACT

One hundred and eighty individually housed piglets with an initial body weight of 7.63 ± 0.98 kg (at 28 days of age) were fed a diet containing either 153, 493, 1022, 1601, 2052 or 2407 mg zinc/kg (added Zn as zinc oxide; ZnO) from day 0-21 post weaning to determine the optimal level of Zn for weaned piglets. Body weight, feed intake and faecal scores were recorded, and blood and faecal samples were collected. Dietary Zn content quadratically affected both feed intake and gain in the first two weeks, with an approximately 1400 mg Zn/kg diet and a Zn intake of 400 mg/day as the optimal levels. The relative risk of diarrhoea increased up to 60% at day 7 and 14 if serum Zn status dropped below the weaning level (767 µg/L), and maintain the weaning serum Zn status required approximately 1100 mg Zn/kg (166 mg Zn/day) during week 1. Blood markers of intestinal integrity (D-lactate and diamine oxidase) were unaffected by dietary Zn, and dietary Zn levels of 1022 and 1601 mg/kg did not affect the faecal numbers of total bacteria, Lactobacilli and E. Coli bacteria compared to 153 mg Zn/kg. These results indicate that the requirement for Zn in newly weaned piglets may be substantially higher than currently assumed.

4.
Scand J Public Health ; 50(7): 914-918, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35548941

ABSTRACT

Denmark has a 35-year history of monitoring health status in the general population through health surveys. In this commentary, we outline the development of health surveys in Denmark from the beginning in 1987 to the present time. We describe how the current systematic framework for the Danish National Health Survey (DNHS) developed. We discuss the methodological basis for the DNHS and describe its application in public health practice and research. Over the years, the DNHS has become an important part of the Danish public health environment. Challenges for the DNHS in the future are to adapt to new trends in public health and at the same time to be able to monitor important changes consistently over time.


Subject(s)
Health Status , Public Health Practice , Denmark/epidemiology , Health Surveys , Humans , Surveys and Questionnaires
5.
J Gen Physiol ; 153(6)2021 06 07.
Article in English | MEDLINE | ID: mdl-33871566
6.
Eur J Neurosci ; 54(8): 6713-6739, 2021 10.
Article in English | MEDLINE | ID: mdl-32464691

ABSTRACT

NMDA receptors are part of the ionotropic glutamate receptor family, and are crucial for neurotransmission and memory. At the cellular level, the effects of activating these receptors include long-term potentiation (LTP) or depression (LTD). The NMDA receptor is a stringently gated cation channel permeable to Ca2+ , and it shares the molecular architecture of a tetrameric ligand-gated ion channel with the other family members. Its subunits, however, have uniquely long cytoplasmic C-terminal domains (CTDs). While the molecular gymnastics of the extracellular domains have been described in exquisite detail, much less is known about the structure and function of these CTDs. The CTDs vary dramatically in length and sequence between receptor subunits, but they all have a composition characteristic of intrinsically disordered proteins. The CTDs affect channel properties, trafficking and downstream signalling output from the receptor, and these functions are regulated by alternative splicing, protein-protein interactions, and post-translational modifications such as phosphorylation and palmitoylation. Here, we review the roles of the CTDs in synaptic plasticity with a focus on biochemical mechanisms. In total, the CTDs play a multifaceted role as a modifier of channel function, a regulator of cellular location and abundance, and signalling scaffold control the downstream signalling output.


Subject(s)
Long-Term Potentiation , Receptors, N-Methyl-D-Aspartate , Neuronal Plasticity , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Signal Transduction , Synaptic Transmission
7.
Poult Sci ; 99(4): 1946-1955, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32241475

ABSTRACT

Providing environmental enrichment for broilers is a potential strategy to increase welfare, activity, and health. The aim of this study was to evaluate the effect of environmental enrichment on health and leg bone characteristics of broilers. One control and 8 types of enrichment were included: 2 distances between food and water (7 and 3.5 m), roughage, vertical panels, straw bales, 2 platforms (30 and 5 cm), and a lowered stocking density (34 kg/m2). Birds were kept according to conventional Danish guidelines. The study included 58 pens with approximately 500 birds each. On day 35 of age, 25 birds per pen were killed and included in a postmortem analysis of wooden breast, body condition scores, pathological conditions (femoral head necrosis, arthritis, tenosynovitis, fractures, tibial dyschondroplasia, and twisted tibiotarsus), muscle width of the lower leg, and tibiotarsus properties (bone strength, weight, length, and proximal diameter, middle diameter, and distal diameter). It was predicted that environmental enrichment would have a positive effect on pathology with the exceptions that environmental enrichment that increased activity would pose a risk factor for wooden breast development, and straw bales would be a risk factor for bacterial infections (arthritis, tenosynovitis, and femoral head necrosis). Furthermore, it was hypothesized that enriched groups would have increased muscle width, bone strength, and dimensions of the tibiotarsus. Broilers with 7 m between food and water had a longer distal diameter of the tibiotarsus than those with straw bales (P = 0.04). The birds provided with vertical panels had wider leg muscle than the treatments with roughage (P = 0.045), 3.5 m distance (P = 0.049), and straw bales (P = 0.044). No effects were found for the remaining outcomes. These results suggest that provision of vertical panels and increased distance between resources can result in larger muscle and bone dimension, possibly having a positive effect on leg health. Furthermore, the provision of environmental enrichment does not appear to be a risk factor for wooden breast or bacterial infection.


Subject(s)
Animal Welfare , Bone Development , Chickens/physiology , Housing, Animal , Animals , Bone and Bones/pathology , Bone and Bones/physiology , Chickens/growth & development , Poultry Diseases/etiology , Poultry Diseases/pathology
8.
Annu Rev Biochem ; 89: 583-603, 2020 06 20.
Article in English | MEDLINE | ID: mdl-31874046

ABSTRACT

P-type ATPases are found in all kingdoms of life and constitute a wide range of cation transporters, primarily for H+, Na+, K+, Ca2+, and transition metal ions such as Cu(I), Zn(II), and Cd(II). They have been studied through a wide range of techniques, and research has gained very significant insight on their transport mechanism and regulation. Here, we review the structure, function, and dynamics of P2-ATPases including Ca2+-ATPases and Na,K-ATPase. We highlight mechanisms of functional transitions that are associated with ion exchange on either side of the membrane and how the functional cycle is regulated by interaction partners, autoregulatory domains, and off-cycle states. Finally, we discuss future perspectives based on emerging techniques and insights.


Subject(s)
Adenosine Triphosphate/chemistry , Copper-Transporting ATPases/chemistry , H(+)-K(+)-Exchanging ATPase/chemistry , Sarcoplasmic Reticulum Calcium-Transporting ATPases/chemistry , Sodium-Potassium-Exchanging ATPase/chemistry , Adenosine Triphosphate/metabolism , Animals , Binding Sites , Cations, Divalent , Cations, Monovalent , Copper-Transporting ATPases/genetics , Copper-Transporting ATPases/metabolism , H(+)-K(+)-Exchanging ATPase/genetics , H(+)-K(+)-Exchanging ATPase/metabolism , Humans , Ion Transport , Models, Molecular , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Protons , Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Single Molecule Imaging , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Substrate Specificity
9.
J Agric Food Chem ; 67(22): 6432-6444, 2019 Jun 05.
Article in English | MEDLINE | ID: mdl-31095381

ABSTRACT

Liquid feeding strategies have been devised with the aim of enhancing grain nutrient availability for livestock. It is characterized by a steeping/soaking period that softens the grains and initiates mobilization of seed storage reserves. The present study uses 2D gel-based proteomics to investigate the role of proteolysis and reduction by thioredoxins over a 48 h steeping period by monitoring protein abundance dynamics in barley-based liquid feed samples supplemented with either protease inhibitors or NADPH-dependent thioredoxin reductase/thioredoxin (NTR/Trx). Several full-length storage proteins were only identified in the water-extractable fraction of feed containing protease inhibitors, illustrating significant inhibition of proteolytic activities arising during the steeping period. Application of functional NTR/Trx to liquid feed reductively increased the solubility of known and potentially new Trx-target proteins, e.g., outer membrane protein X, and their susceptibility to proteolysis. Thus, the NTR/Trx system exhibits important potential as a feed additive to enhance nutrient digestibility in monogastric animals.


Subject(s)
Animal Feed/analysis , Hordeum/enzymology , Plant Proteins/chemistry , Thioredoxin-Disulfide Reductase/chemistry , Thioredoxins/chemistry , Electrophoresis, Gel, Two-Dimensional , Food Handling , Hordeum/chemistry , Plant Extracts/chemistry , Plant Extracts/metabolism , Plant Proteins/metabolism , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Proteomics , Seeds/chemistry , Seeds/enzymology , Thioredoxin-Disulfide Reductase/metabolism , Thioredoxins/metabolism
10.
J Sci Food Agric ; 99(7): 3628-3634, 2019 May.
Article in English | MEDLINE | ID: mdl-30628081

ABSTRACT

BACKGROUND: Phosphorus (P) supply is essential for bone mineralisation. Reduced P may result in osteopenia, whereas excessive P may result in environmental impacts. The objective was to study the long-term effect of three dietary P levels on net bone mineralisation in growing-finishing pigs. Eighteen female pigs were fed low P (LP (4.1)), medium P (MP (6.2)) or high P (HP (8.9 g P kg-1 DM)) from 39.7 until 110 kg. Trabecular, cortical and overall bone mineral density (BMD), ash, calcium (Ca) and P were determined after slaughter. RESULTS: The LP diet generally reduced the BMD, ash, Ca and P in all bones, though all measures were markedly lowered in femur compared with humerus. The trabecular BMD in LP pigs was only different in the distal section compared to the MP-fed pigs (P < 0.05). In addition, ash, Ca and P were lower in the proximal and distal sections. No significant effect of HP was seen. Conclusively, LP caused lower net bone mineralisation, mainly of femur. The trabecular tissue of the distal bones seems to be most metabolically active. CONCLUSIONS: The MP level was sufficient for net bone mineralisation. Femur is recommended for studying bone fragility whereas humerus seems useful to study increased P retention. © 2019 The Authors. Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Subject(s)
Bone and Bones/metabolism , Phosphorus, Dietary/metabolism , Swine/metabolism , Animal Feed/analysis , Animals , Bone Density , Bone Development , Calcium, Dietary/analysis , Calcium, Dietary/metabolism , Female , Phosphorus, Dietary/analysis , Swine/growth & development
11.
J Anim Sci ; 97(1): 231-245, 2019 Jan 01.
Article in English | MEDLINE | ID: mdl-30312406

ABSTRACT

The aims of this study were to investigate 1) the effect of high dietary fiber (DF; 19.3% to 21.7%) supplemented to late gestating sows on mammary uptake and metabolism of energy substrates as well as colostrum production and 2) the ontogeny of colostral fat and lactose synthesis using mammary carbon balance, and colostral protein using IgG as a biomarker. Sows were fed either a control diet (CON) consisting of a standard gestation diet (14.6% DF) until day 108 of gestation and a transition diet (16.8% DF) from day 109 of gestation until farrowing or a high DF treatment where part of the daily ration was replaced with a high DF supplement (FIB). The FIB sows received 19.3% and 21.7% DF in the last 2 wk prior to farrowing. Sows were surgically implanted with permanent indwelling catheters at day 75 ± 2 of gestation and blood samples were collected at 6 different time points in late gestation and at 11 different time points within 24 h after the onset of farrowing. Colostrum samples were collected at 0, 12, and 24 h after the onset of farrowing. Arterial concentration of acetate (P = 0.05) and colostral fat content (P = 0.009) were greater in FIB sows compared with CON sows. Plasma IgG dropped from day -10 relative to farrowing (P < 0.001), suggesting an uptake by the mammary glands. Mammary plasma flow (P = 0.007) and net mammary uptake of glucose (P = 0.04) increased during farrowing while dietary treatment had no effect on net mammary uptake of other energy substrates during late gestation and farrowing. The net mammary uptake of carbon from glucogenic precursors did not equate to the sum of carbons secreted in colostral lactose and released as CO2, indicating that carbons from ketogenic precursors were likely used for colostral fat and for oxidation. Mammary nonprotein carbon uptake matched the mammary output, indicating that the majority of colostral fat and lactose were produced after the onset of farrowing. In conclusion, high DF included in the diet for late gestating sows increased colostral fat content by 49% but this substantial dietary response could not be explained by the increased carbon uptake from short chain fatty acids during the colostral period. The nonprotein carbon balance of mammary glands during farrowing suggests that the majority of colostral fat and lactose were produced after the onset of farrowing, whereas the drop in plasma IgG in late gestation suggests that the mammary glands take up this colostral component prior to farrowing.


Subject(s)
Colostrum/metabolism , Lactation/physiology , Mammary Glands, Animal/physiology , Pregnancy, Animal , Swine , Animal Feed , Animal Nutritional Physiological Phenomena , Animals , Body Fluids , Diet/veterinary , Dietary Fiber/metabolism , Female , Lactose/metabolism , Pregnancy , Pregnancy, Animal/physiology
12.
Brain ; 141(12): 3308-3318, 2018 12 01.
Article in English | MEDLINE | ID: mdl-30423015

ABSTRACT

Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the α2 subunit of the Na+/K+-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na+ and K+ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K+ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene.


Subject(s)
Hypokalemic Periodic Paralysis/genetics , Hypokalemic Periodic Paralysis/physiopathology , Sodium-Potassium-Exchanging ATPase/genetics , Animals , Child , Humans , Hypokalemic Periodic Paralysis/pathology , Male , Membrane Potentials , Muscle, Skeletal/pathology , Mutation, Missense , Potassium/physiology , Sodium-Potassium-Exchanging ATPase/physiology , Xenopus laevis
13.
J Anim Sci ; 96(11): 4693-4703, 2018 Nov 21.
Article in English | MEDLINE | ID: mdl-30085053

ABSTRACT

Phosphorus (P) is essential for building and maintaining a healthy and strong skeleton. Moreover, dietary P supply may play a role for bone turnover, and the excretion of bone turnover metabolites may be useful as markers for sufficient dietary P supply. The objective was to study the long-term effects of low, medium, and high dietary P supply on bone metabolism in terms of serum concentration and urinary excretion of bone turnover components and metabolites in healthy growing-finishing pigs compared with bone mineral content (BMC) and bone mineral density (BMD) of humerus and femur. Pigs were fed diets containing low [LP; 4.1 g/kg dry matter (DM)], medium (MP; 6.2 g/kg DM), or high dietary P (HP; 8.9 g/kg DM) from 39.7 kg body weight (BW) until slaughter at 110 kg BW. Urine and blood were collected at 40, 70, and 110 kg BW while bones were collected at slaughter. Serum was analyzed for osteocalcin (OC), bone alkaline phosphatase (BAP), and C-terminal telopeptides of type I collagen (CTX-I), whereas urine was analyzed for pyridinoline (PYD), deoxypyridinoline (DPD), CTX-I, hydroxylysine (HYL), galactosyl-hydroxylysine (GAL-HYL), glycosyl-galactosyl-hydroxylysine (GLC-GAL-HYL), and hydroxyproline (HYP). Humerus and femur were analyzed for BMC and BMD. The LP diet caused reduced OC and increased BAP and CTX-I concentrations in serum. Furthermore, BAP was increased in response to the HP diet. Urine metabolites of bone resorption were all increased in pigs fed the LP diet, but only a few responses were obtained in response to the HP diet. Furthermore, age-related decreases were identified for BAP, HYL, GAL-HYL, and GLC-GAL-HYL. Bone mineral content and BMD were markedly lowered in pigs fed the LP diet but were not affected in pigs fed the HP diet. In conclusion, OC, BAP, and CTX-I in serum have proved useful for P adequacy in growing-finishing pigs. In addition, urine bone resorption metabolites have also proved useful for P adequacy and analysis of PYD, DPD, and CTX-I was considered to be the most relevant markers due to their specificity for bone and their negative correlation with BMD, BMC, ash, calcium (Ca), and P contents. Finally, DPD may be the preferred marker in long-term P feeding assessments.


Subject(s)
Biomarkers/analysis , Bone Density/drug effects , Calcium, Dietary/pharmacology , Phosphorus, Dietary/pharmacology , Swine/physiology , Animal Feed/analysis , Animals , Body Weight/drug effects , Bone Resorption/drug therapy , Bone and Bones/drug effects , Bone and Bones/physiology , Diet/veterinary , Female
15.
J Trace Elem Med Biol ; 49: 231-240, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29402502

ABSTRACT

Zinc is an essential trace element, highly important for a well functioning immune system. In case of zinc deficiency, proper immune functions are not ensured thus leading to various diseases. Weaning of pigs from the sow causes stress, increasing susceptibility to infections. Moreover, low feed intake during the first two weeks post-weaning, accompanied by low zinc intake, results in temporary zinc deficiency. Therefore, supporting the immune system by zinc supplementation might improve its function and thereby the pigs' health and well-being. In this study, the immune status of weaned pigs was analyzed under different conditions of zinc supplementation. More precisely, the daily porcine diet was either left unsupplemented (0 ppm), or was supplemented with low (100 ppm), or high (2500 ppm) amounts of additional zinc in the form of zinc oxide (ZnO) (Zn0, Zn100, and Zn2500, respectively). Porcine innate and adaptive immune cells of the different dietary groups were analyzed. Results revealed an improved innate immune capacity, represented by increased phagocytosis and slightly increased oxidative burst in cells from the Zn2500 pigs and Zn100 pigs, respectively. Apart from that, zinc supplementation improved adaptive immunity, as seen by increased numbers of CD3+ T cells as well as increased numbers of CD3+CD4+Foxp3+ regulatory T cells, elevated interleukin (IL)-2 production and decreased IL-10 production. Although not significant, supplementing 2500 ppm zinc slightly decreased killing activity of natural killer (NK) cells. Thus, the optimal concentration for zinc supplementation of weaned pigs two weeks post-weaning needs to be further studied, presumably establishing an optimal concentration between 100 ppm and 2500 ppm zinc. Genome comparisons indicate that the porcine genome is more closely related to the human genome than the murine genome is related to the human genome. Therefore, the pig seems to be a suitable organism to study human immunity and diseases. Results obtained in the current study might therefore be transferable to the human immune system.


Subject(s)
Weaning , Zinc Oxide/pharmacology , Zinc/pharmacology , Adaptive Immunity/drug effects , Animals , Copper/pharmacology , Dietary Supplements , Female , Interleukin-10/metabolism , Interleukin-2/metabolism , Male , Respiratory Burst/drug effects , Swine , T-Lymphocytes, Regulatory
16.
Hum Genet ; 137(2): 111-127, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29305691

ABSTRACT

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.


Subject(s)
Cerebellar Ataxia/genetics , Foot Deformities, Congenital/genetics , Hearing Loss, Central/genetics , Hearing Loss, Sensorineural/genetics , Optic Atrophy/genetics , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Adolescent , Adult , Cerebellar Ataxia/epidemiology , Cerebellar Ataxia/physiopathology , Child , Child, Preschool , Denmark/epidemiology , Female , Foot Deformities, Congenital/epidemiology , Foot Deformities, Congenital/physiopathology , Germany/epidemiology , Hearing Loss, Central/epidemiology , Hearing Loss, Central/physiopathology , Hearing Loss, Sensorineural/epidemiology , Hearing Loss, Sensorineural/physiopathology , Humans , Male , Molecular Dynamics Simulation , Mutation, Missense/genetics , Optic Atrophy/epidemiology , Optic Atrophy/physiopathology , Phenotype , Retrospective Studies , Sodium-Potassium-Exchanging ATPase/chemistry , Sweden/epidemiology , Young Adult
17.
Front Physiol ; 8: 371, 2017.
Article in English | MEDLINE | ID: mdl-28634454

ABSTRACT

The sodium and potassium gradients across the plasma membrane are used by animal cells for numerous processes, and the range of demands requires that the responsible ion pump, the Na,K-ATPase, can be fine-tuned to the different cellular needs. Therefore, several isoforms are expressed of each of the three subunits that make a Na,K-ATPase, the alpha, beta and FXYD subunits. This review summarizes the various roles and expression patterns of the Na,K-ATPase subunit isoforms and maps the sequence variations to compare the differences structurally. Mutations in the Na,K-ATPase genes encoding alpha subunit isoforms have severe physiological consequences, causing very distinct, often neurological diseases. The differences in the pathophysiological effects of mutations further underline how the kinetic parameters, regulation and proteomic interactions of the Na,K-ATPase isoforms are optimized for the individual cellular needs.

18.
PLoS One ; 12(1): e0170043, 2017.
Article in English | MEDLINE | ID: mdl-28081252

ABSTRACT

BACKGROUND: Phosphorus (P) levels in refeeding diets are very important as undernourished children are at risk of hypophosphatemia during refeeding. For this reason, conventional corn-soy-blends (CSB) have been reformulated by the World Food Programme to obtain a mono-calcium-phosphate fortified product (CSB+) and a product further fortified with skim milk powder (CBS++). METHODS: Using a piglet model of undernourished children, we hypothesized that feeding of CSB+, CSB++ or CSB+ with added whey permeate (CSB+/wp) would help to prevent refeeding hypophosphatemia. Pigs were weaned at 4 weeks of age and undernutrition was induced with a nutritionally inadequate pure maize diet for 7 weeks, after which they were refed for 3 weeks with either CSB+ (n = 10), CSB++ (n = 10) or CSB+/wp (n = 10). For reference, a fourth group continued on the maize diet (REF, n = 10). RESULTS: Following induction of undernutrition, body weight and length were 29±5% and 67±4% (means±SD) of values in age-matched pigs fed a nutritionally adequate diet, and the mean serum P level was 1.77±0.34 mmol/l. During the first week of refeeding, P levels in the CSB+ pigs decreased to 55% of values before refeeding (P < 0.05) while values in the CSB++ and CSB+/wp pigs were able to maintain their plasma phosphate at a similar level as before refeeding. CONCLUSION: We conclude that fortification of CSB with only monocalcium-phosphate does not prevent hypophosphatemia. Dairy products like skim milk powder or whey permeate may represent relevant sources of phosphorus during refeeding. The content and form of phosphorus in such diets need to be carefully evaluated, and the undernourished piglet may be used to test the efficacy of such diets.


Subject(s)
Diet/veterinary , Glycine max/chemistry , Hypophosphatemia/veterinary , Malnutrition/veterinary , Phosphorus/chemistry , Zea mays/chemistry , Animals , Body Size , Body Weight , Calcium/urine , Female , Food, Fortified , Hypophosphatemia/pathology , Hypophosphatemia/prevention & control , Magnesium/blood , Malnutrition/complications , Malnutrition/pathology , Phosphorus/blood , Phosphorus/urine , Serum Albumin/analysis , Glycine max/metabolism , Swine , Zea mays/metabolism
19.
J Sci Food Agric ; 97(1): 244-251, 2017 Jan.
Article in English | MEDLINE | ID: mdl-26996813

ABSTRACT

BACKGROUND: To increase self-supply of protein and phosphorus (P) in European pig and poultry diets and reduce nitrogen (N) and P excretion, attention is directed to approaches increasing protein and P digestibility of rapeseed, sunflower and faba beans. Wheat bran is rich in enzymes degrading and solubilizing protein and phytate. Herein, solubilization of protein, N and P was investigated when increasing ratios of wheat bran were fermented with rapeseed meal (RSM), sunflower meal (SFM), faba beans (FB) or a combination of these (RSM/SFM/FB). RESULTS: Protein, N and P solubility was greater, for all mixtures, the more wheat bran was included and the longer the mixtures were fermented. The increase in N (FB > RSM/SFM/FB > SFM > RSM) and protein solubility (RSM/SFM/FB > RSM > SFM > FB) was greatest from day 0 to day 3 and thereafter limited, whereas P solubility increased during the whole period (5 days; FB > RSM/SFM/FB > SFM > RSM). In general, FB showed the highest solubility and highest increase in N and P solubility, while RSM showed the highest protein solubility and RSM/SFM/FB the highest increase in protein solubility. CONCLUSION: Fermentation of RSM, SFM, FB and RSM/SFM/FB without or with wheat bran uncovers a potential for increased protein and P digestibility and thereby reduced N and P excretion from pigs and poultry. © 2016 Society of Chemical Industry.


Subject(s)
Animal Feed/analysis , Dietary Fiber , Dietary Proteins/analysis , Fermentation , Phosphorus, Dietary/analysis , Animal Nutritional Physiological Phenomena , Animals , Brassica rapa , Diet/veterinary , Digestion , Helianthus , Poultry , Solubility , Sus scrofa , Vicia faba
20.
J Agric Food Chem ; 65(2): 281-290, 2017 Jan 18.
Article in English | MEDLINE | ID: mdl-28004575

ABSTRACT

The angiopoietin-like 4 (ANGPLT4) protein is involved in lipid metabolism and is known to inhibit lipoprotein lipase in the bloodstream. We investigated the effect of milk on intestinal ANGPTL4 and the metabolic profile of growing pigs and the effect of free fatty acids (FFAs) on ANGPTL4 in ex vivo and in vitro assays. Feeding pigs whole milk increased intestinal ANGPTL4 mRNA and increased fecal excretion of long-chain FFA compared to the control group fed soybean oil (n = 9). Furthermore, FFAs (C4-C8) induced ANGPTL4 gene expression in porcine intestinal tissue mounted in Ussing chambers and ANGPTL4 protein secretion to both the apical and basolateral sides of intestinal Caco-2 cells on permeable membranes. Altogether, these results support an ANGPTL4-induced secretion of fecal FFAs. Urinary levels of FFAs (C4-C12), 3-hydroxyadipic acid, and suberic acid were also increased by milk consumption, indicating higher energy expenditure compared to the control group.


Subject(s)
Angiopoietins/metabolism , Fatty Acids/pharmacokinetics , Feces/chemistry , Intestinal Mucosa/metabolism , Milk , Angiopoietin-Like Protein 4 , Angiopoietins/genetics , Animals , Caco-2 Cells , Diet , Fatty Acids/metabolism , Fatty Acids/urine , Female , Gene Expression Regulation , Humans , Soybean Oil/pharmacology , Sus scrofa
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